ES2371825T3 - COMPOSITIONS FOR THE TREATMENT OF VAGINAL INFECTIONS WITH CHRONIC INFLAMMATION. - Google Patents

Abstract

The present invention relates to compositions based on benzofuran compounds and benzophenanthridine alkaloids, which possess antiinflammatory, antibacterial and antifungal activity useful in the treatment of vaginal infections and the resulting inflammatory states.

Description

Compositions for the treatment of vaginal infections with chronic inflammation.

5 Summary

The present invention relates to compositions based on benzofuran compounds and benzophenantridine alkaloids, which have anti-inflammatory, antibacterial and antifungal activity useful in the treatment of vaginal infections and the resulting inflammatory conditions.

Prior art

Vaginitis is often initially asymptomatic, but over time it can degenerate into infections that can be dangerous. Vulvovaginal infections, whether of viral, bacterial, fungal or protozoan origin (herpes,

15 trichomoniasis, candidiasis) cause vulvar itching, stinging, irritation and injuries, followed by external dysuria and vulvar dyspareunia. Vaginitis can lead to a series of serious events, with recurrent infections, such as toxicity in other organs and devices. This phenomenon is particularly important in many developing countries, where these events predispose the patient to the risk of contracting HIV or other sexually transmitted diseases.

Trichomoniasis presents symptoms such as purulent, yellowish exudate, with vulvar irritation, inflammation of the vaginal and vulvar epithelium and petechial lesions of the cervix. The pH of the secretion is greater than 5, thus promoting the development of trichomonas. In candidiasis there is severe vulvar itching with erythema and edema and the secretions are smelly, as in the case of bacterial vaginitis. These disorders are treated with antifungals and

25 oral antibiotics administered at high doses or with gels for local treatment. These treatments always last a long time and can have side effects.

Benzophenantridine alkaloids isolated from Macleaya cordata, Macleaya microcarpa, Sanguinaria canadensis and Chelidonia majus are particularly active in strains directly involved in vaginal infections, such as Trichomonas vaginalis, Escherichia coli, Pseudomonas aeruginosa and the like.

According to the invention, benzofuran compounds have the following formula

Wherein R may be hydrogen or a linear or branched alkyl chain having from 2 to 6 carbon atoms, or an alkyl chain substituted with nitro, amine groups; R is preferably hydrogen or C1-C3 alkyl.

Said benzofuran compounds are known and can be prepared by conventional methods, for example by reacting a phenol suitably substituted with 2-phenoxy-2 ', 4'-dimethoxyacetophenone under the conditions reported in Chimie Therapeutique 1973, 8, 398, followed by cyclization in the presence of polyphosphoric acid in xylene and hydrolysis of the methoxyl and hydroxyl groups. The benzofuran compounds used in the compositions according to the invention have structural formula 1 and have a potent antibacterial and antifungal action against numerous strains of Candida.

Description of the invention

The present invention relates to compositions based on:

a) benzophenantridine alkaloids; Y

b) benzofuran compounds;

and possibly

C) extract of Zanthoxylum bungeanum or Echinacea angustifolia;

They have anti-inflammatory, antibacterial and antifungal activity useful in the treatment of vaginal infections and the resulting inflammatory conditions, especially vaginitis of various origins with associated inflammatory problems.

More particularly, the present invention relates to formulations based on:

a) benzophenantridine alkaloids selected from sanguinarine and / or queleritrine and / or derivatives thereof; Y

b) benzofuran compounds as specified above;

and possibly

c) Zanthoxylum bungeanum or Echinacea angustifolia extract.

It has now surprisingly been found that the compositions according to the invention have an antibacterial, antifungal and antienzyme activity greater than the sum of the various components administered separately. This effect may be due to a mechanism of synergistic action that takes place between the various components of the association in question. The compositions according to the invention quickly eliminate these infections, eliminating the presence of saprophyte and reducing inflammation, itching and vaginal pH.

According to the invention, the compositions will contain the various components at the following intervals (by weight per unit dose):

a) benzophenantridine alkaloids: from 0.15 mg to 15 mg; Y

b) benzofuran compounds: from 0.2 to 25 mg;

and possibly

c) Zanthoxylum bungeanum or Echinacea angustifolia extract: from 0.1 to 10 mg.

According to a particularly preferred aspect, the compositions in question will contain the various components within the following ranges (by weight per unit dose):

a) benzophenantridine alkaloids: from 0.4 to 10 mg; Y

b) benzofuran compounds: from 0.4 to 10 mg;

and possibly

c) Zanthoxylum bungeanum or Echinacea angustifolia extract: from 0.2 to 5 mg.

The benzophenantridine alkaloids sanguinarina and queleritrina can be present in salified or free form, as such in substantially pure form or in the form of extracts of Sanguinaria canadensis, Macleaya cordata, Macleaya microcarpa or Chelidonia majus. According to a preferred aspect, benzophenantridine alkaloids will be present in salified form with luteic acid. It has been found that said salts, which are prepared by reacting the sulfates or chlorides of the alkaloids with the sodium or potassium salt of luteic acid and subsequent crystallization, are particularly effective for the purposes of this invention. In particular, sanguinarine is a potent anti-angiogenesis factor that helps reduce inflammation (Jong-Pil Eun 2004). In vivo, sanguinarine suppresses capillary formation in Matrigel and in the chorioallantoid membrane in chicken embryo (Jong-Pil Eun 2004).

Such benzophenantridine alkaloids not only have considerable antibacterial, antifungal and antitricomonas activity, but also have considerable activity against cytomegalovirus and papillomavirus. For this reason, the archetypes of these alkaloids, sanguinarine, cheleritrine and chelidonine, which also have an analgesic effect, are very useful in the treatment of vaginitis of different etiologies. These compounds act in synergy with each other to reduce inflammation, and consequently symptoms, and suppress the disorder.

The compounds with a benzofuran structure described above may be present as such or in the form of extracts containing them, such as extracts of Krameria triandra, Eupomatia laurina and Piper sp. Compounds isolated from Krameria triandra that have been shown to be particularly active are eupomatenoid 6 and neolignan 2- (2,4-dihydroxyphenyl) -5- (E) -propenyl-benzofuran, which have shown antibacterial and antifungal activity in numerous Gram + bacteria strains, fungi and anaerobic bacteria.

According to a particularly preferred aspect, the compositions in question will also contain an extract of Zanthoxylum bungeanum or Echinacea angustifolia to help eliminate itching and / or pain, when present. This action is due to the presence of isobutylamides that bind to CB2 and CB1 cannabinoid receptors. The formulations according to the invention can be prepared according to well-known conventional methods, such as those described in "Remington's Pharmaceutical Handbook", Mack Publishing Co., N.Y., USA, together with suitable excipients.

The compositions according to the invention will be conveniently formulated in water / oil emulsions with others.

5 compatible excipients for external treatment of the anogenital region; For internal treatments the compounds will be suspended in oils in soft gelatin capsules that disintegrate easily after introduction into the vaginal canal.

Examples of formulations according to the invention include creams, ointments, powders, lotions and the like, vaginal ovules or equivalent formulations, including capsules that dissolve at internal body temperature.

The examples set forth below illustrate the invention, without limiting its scope.

Example 1 - Preparation of benzofuran compounds

15 Stage A. Preparation of 2-phenoxy-2 ’, 4’-dimethoxyacetophenone (a)

A solution of 2-bromo-2 ', 4'-dimethoxyacetophenone (5 g, 19.1 mmol) in 25 ml of 2-butanone was added to a phenol suspension (1.8 g, 19.1 mmol), K2CO3 (2.6 g, 19.1 mmol) and Kl (41.5 mg, 0.25 mmol) in 20.0 ml of the same solvent. Then the solution was refluxed for 20 hours. The mixture was filtered and the solvent removed in vacuo. The residue obtained was dissolved in EtOAc and washed with a 10% aqueous solution of NaOH and then with water. The organic extract was dried over Na2SO4, filtered and evaporated in vacuo. Finally, the crude residue was washed with Et2O and dried under low pressure to provide 4.4 g (yield: 84%) of the title compound.

25 Stage B. Preparation of 2- (2 ’, 4’-dimethoxyphenyl) benzofuran (b)

12 g of polyphosphoric acid was added to a solution of the compound obtained in step A (4.4 g, 16.2 mmol) in 130.0 ml of xylene. The mixture was refluxed for 2 hours and then allowed to cool to room temperature. Then the solution was decanted and evaporated under low pressure. The resulting residue was used (3.7 g,

30 yield: 90%) in the next stage without further purification.

Stage C. Preparation of 2- (2 ’, 4’-dihydroxyphenyl) benzofuran (1)

A mixture of the compound prepared in step B (3.7 g, 14.5 mmol) and pyridine hydrochloride (11.1 g, was heated

96.4 mmol) to 225 ° C for 45 minutes. The red product formed in 10% HCl was poured. The mixture was washed repeatedly with EtOAc; The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by column chromatography (hexane / EtOAc = 7: 3) to provide the final compound that was obtained in a yield of 41% (1.36 g) after crystallization from benzene.

40 Formulation example 1

Oily suspension for soft gelatin capsules to be inserted into the vaginal canal

Lipophilic extract of Macleaya cordata (75%) 10 mg 2,4-Dihydroxyphenyl-3-benzofuran 10 mg Soy Lecithin 60 mg Beeswax 50 mg Vegetable oil c.s.p. up to 800 mg

45 Formulation example 2

Cream (oil in water emulsion)

Krameria triandra extract 0.4 g Macleaya cordata alkaloid fraction 0.4 g Zanthoxylum bungeanum 0.2 g lipophilic extract Propylene Glycol 10.00 g Isopropyl Myristate 5.00 g Cetyl alcohol 5.00 g Polysorbate 80 3.00 g Carbomer 0.40 g Methyl parahydroxybenzoate 0.10 g Propyl parahydroxybenzoate 0.05 g Purified water c.p.s. up to 100 g

Formulation Example 3

Vaginal ovum

2,4-Dihydroxyphenyl-3-benzofuran Macleaya alkaloid fraction Glycerides of fatty acids c.p.s. until

 10 mg 3 mg 2.0 g

Claims (10)

1. Compositions based on: a) benzophenantridine alkaloids; Y b) benzofuran compounds of the formula In which R may be hydrogen or a linear or branched alkyl chain having from 2 to 6 carbon atoms, or an alkyl chain substituted with nitro, amine groups; and possibly 15 c) Zanthoxylum bungeanum or Echinacea angustifolia extract. 2. Compositions according to claim 1, based on: a) benzophenantridine alkaloids selected from sanguinarine, cheleritrine or chelidonine or derivatives thereof; Y b) benzofuran compounds as specified above; and possibly 25 c) Zanthoxylum bungeanum or Echinacea angustifolia extract. 3. Compositions according to claims 1 and 2, wherein the various components are present at the following intervals (by weight per unit dose): 30 a) benzophenantridine alkaloids: from 0.15 mg to 15 mg; Y b) benzofuran compounds: from 0.2 to 25 mg; 35 and possibly c) Zanthoxylum bungeanum or Echinacea angustifolia extract: from 0.1 to 10 mg. 4. Compositions according to claim 3, wherein the various components are present at the following intervals (by weight per unit dose): a) benzophenantridine alkaloids: from 0.4 to 10 mg; I b) benzofuran compounds: from 0.4 to 10 mg; 45 and possibly c) Zanthoxylum bungeanum or Echinacea angustifolia extract: from 0.2 to 5 mg. Compositions according to the preceding claims, in which the benzophenantridine sanguinarine and cheleritrin alkaloids are present in salified or free form, as such in substantially pure form or in the form of extracts of Sanguinaria canadensis, Macleaya cordata, Macleaya microcarpa or Chelidonia majus . 6. Compositions according to claim 5, wherein the benzophenantridine alkaloids are present in salified form with luteic acid.

7.

Compositions according to claims 1-4, wherein the benzofuran compounds of formulas 1 and 2 are present as such or in the form of extracts containing them.

8.

Compositions according to claim 7, wherein the benzofuran compounds are present in the form of extracts of Krameria triandra, Eupomatia laurina and Piper sp.

9.

Formulations according to any one of claims 1 to 8, in the form of water / oil emulsions,

5 softgel capsules, vaginal suppositories or equivalent formulations, creams, ointments, powders, lotions and the like. 10. Use of: 10 a) benzophenantridine alkaloids; Y b) benzofuran compounds; and possibly 15 c) Zanthoxylum bungeanum or Echinacea angustifolia extract for the preparation of topical formulations for the treatment of vaginal infections and the resulting inflammatory conditions. twenty 11. Use according to claim 10, wherein the vaginal infections are vaginitis of various origins with associated inflammatory problems.